The p.Gly622Asp (G622D) mutation, frequently found in Reunion Island and in black populations, is associated with a wide spectrum of CF and CFTR-RD phenotypes

Abstract

Examination of genotype-phenotype correlations along with functional evaluation of CFTR mutations may not be straightforward. The c.1865G>A, p.Gly622Asp (G622D), located at the NBD1 C terminus of the CFTR protein, was initially reported in patients with male infertility. However, the substitution of Gly622 by an aspartic acid in vitro would perturb the local structure or even affect the CFTR folding itself. In order to determine whether p.Gly622Asp affects the risk of developing a CFTR-Related disorder (CFTR-RD) or cystic fibrosis (CF), we analyzed the phenotype of subjects bearing the p.Gly622Asp mutation. We report molecular and clinical analyses in eleven unrelated patients with CF or CFTR-RD with compound heterozygosity for the p.Gly622Asp mutation. On the basis of the clinical features presented by the eleven patients, we postulate that the p.Gly622Asp might be associated with a wide spectrum of phenotypes including classical cystic fibrosis.

Functional Assays Are Essential for Interpretation of Missense Variants Associated with Variable Expressivity

“…10,28 Variant G622D (c.1865G>A [p.Gly622Asp]) permitted higher amounts of CFTR function at 18.2% of WT-CFTR function, consistent with its partial expressivity. 29 Finally, the substitution of cysteine for phenylalanine at codon 508 (F508C [c.1523T>G (p.Phe508Cys)]) had no reduction of CFTR function in two CFBE cell lines (mean 114% WT). F508C has been shown to have a minimal effect on CFTR folding and function, 30 consistent with evidence that F508C does not cause disease when found in healthy CF carriers of F508del.…”

Cystic fibrosis: the urgent need to report on mutations among patients of African descent

“…[4] This mutation (3120+1G>A) is now routinely tested for in selected medical genetic settings in South Africa (SA). [5] The investigation of specific CFTR mutations in various populations of non-European ancestry is gaining increasing attention globally, especially in countries that, like SA, have a population of diverse ethnic background, such as Reunion Island, [6] Brazil [7] and the USA. [2] This research is shedding light on ethnic-specific variants that cannot be detected by the routinely used 30-mutation CFTR panel.…”